Urine 5-HIAA and quality of life in neuroendocrine neoplasia. Is there an association?

Introduction

Neuroendocrine neoplasms (NEN) are a heterogeneous group of epithelial tumours, classified into indolent well-differentiated neuroendocrine tumours (NETs) and relatively aggressive poorly-differentiated neuroendocrine carcinomas (NECs). 1 While NEN are uncommon, their prevalence now exceeds that of many upper gastrointestinal (GI) cancers owing to increasing incidence and prolonged survival. 2 Approximately 30-45% of NEN are functioning tumours that secrete bioactive compounds causing distinct clinical syndromes; the most recognised of which is carcinoid syndrome 3

Serotonin is the principal hormone among approximately 40 vasoactive substances secreted by NEN, that contributes to the typical symptoms of carcinoid syndrome including, diarrhoea (80% of patients), flushing (50-85%), abdominal pain (40%), and wheeze (10-20%). 4 Serotonin undergoes hepatic inactivation into its final renally-excreted metabolite u5HIAA ( Figure 1 ). Carcinoid syndrome predominantly arises in patients with small bowel NEN and liver metastases, where hepatic inactivation of serotonin is impaired, resulting in systemic accumulation; however it may also arise with primary bronchial, pancreatic and pelvic NENs, without liver metastases. Carcinoid syndrome is associated with reduced overall survival and a worse quality of life. 3 Elevated systemic serotonin levels are also associated with fibrotic complications, including carcinoid heart disease and mesenteric fibrosis. 4 Figure 1. Pathways of tryptophan and serotonin metabolism.

Urine 5-HIAA, the primary metabolite of serotonin, is a key diagnostic biomarker for carcinoid syndrome, correlating with tumour size and metastatic burden 5 Whilst many NEN centres continue to use 24-hour urine collections, random 10 ml u5HIAA correlate well with 24-hour urinary values and is more practical for patients and biochemists. 6 In clinical practice, reduction in u5HIAA is often interpreted as evidence of biochemical response to treatment with somatostatin analogues. The PROMID trial demonstrated that Octreotide increased progression-free survival, alleviated carcinoid syndrome symptoms, and reduced urine 5-HIAA in patients with small bowel NETs. 7 However, there is limited evidence to demonstrate that low u5HIAA levels are associated with improved symptoms and better quality of life in patients with NEN.

Patients with NEN may experience impaired health-related quality of life (HRQL) because of tumour burden, treatment effects, gastrointestinal symptoms, endocrine symptoms and psychological distress. Validated patient-reported outcome measures allow these domains to be assessed systematically. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire is validated for assessing HRQL in cancer patients, with higher global health scores reflecting better quality of life and higher symptom scores indicating greater symptom severity. 8 The QLQ-GINET21 module complements the QLQ-C30 by assessing endocrine, gastrointestinal, and treatment-related symptoms, alongside social functioning and disease-related concerns specific to NEN. 9 Psychological well-being is equally integral to comprehensive cancer care, with tools like Patient Health Questionnaire-9 (PHQ-9) 10 and Generalized Anxiety Disorder-7 (GAD-7) 11 widely validated for assessing depression and anxiety respectively. Identifying whether a routinely used biomarker such as u5HIAA relates to these outcomes could help clarify its clinical relevance beyond biochemical monitoring.

The relationship between serotonin biology and psychological symptoms in NEN remains uncertain. Peripheral serotonin does not cross the blood-brain barrier, and most serotonin in the body is synthesised outside the central nervous system. 12 It has been proposed that excess peripheral serotonin production may deplete tryptophan availability for central serotonin synthesis and thereby contribute to psychological distress, but this remains a hypothesis rather than an established causal mechanism. 13 , 14 Several studies have observed increased psychological distress in patients with NEN and carcinoid syndrome ( Table 1 ), however a consistent association between u5HIAA and mental health outcomes in NEN has not been established. This study used validated questionnaires to examine whether spot u5HIAA concentrations are associated with HRQL, gastrointestinal and endocrine symptom burden, anxiety and depression in patients with NEN. Table 1. Summary of previous studies evaluating psychological symptoms and health-related quality of life in patients with neuroendocrine neoplasms. Reference Number of patients Outcome measured Key findings 15 22 Hamilton rating scale for depression 50% patients had depressive symptoms 16 24 EORTC- QLQC30 Anxiety scores improved with SSAs. Levels of tumour markers were not related to HRQL 17 14 CANTAB n europsychological battery Sustained visual attention was impaired. 18 20 Structured psychiatric interview 75% of patients fulfilled diagnostic DSM-IV criteria for a disorder of impulse control. 19 50 Hospital Anxiety and Depression Scale 25% had high anxiety scores, unrelated to u5HIAA levels

Methods

This was a retrospective cross-sectional study of systematically collected quality of life data and temporally-related biomarkers conducted in the outpatient setting in a tertiary centre in London.

Quality of life data were collected for 386 patients with a histological or radiological diagnosis of NEN between January 2014 and November 2021 within King’s Health Partners ENETS Centre of Excellence. The site includes two acute NHS Hospital Trusts (King’s College Hospital NHS Foundation Trust and Guy’s and St. Thomas’ NHS Foundation Trust), and a NHS Mental Health Trust (South London and the Maudsley NHS Foundation Trust). Patient reported quality of life data were made available through the Integrating Mental and Physical Healthcare: Research, Training and Services (IMPARTS) database 20

The study was conducted in accordance with the Declaration of Helsinki, and approved by the IMPARTS Research Oversight Committee of King’s Health Partners (date of approval: 27/11/2020). IMPARTS holds lasting approval from the Health Research Authority (HRA) to independently approve projects under an agreed research governance framework. Informed consent was obtained from all subjects involved in the study via the IMPARTS database and all survey data were pseudonymized by IMPARTS. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 21

u5HIAA analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the United Kingdom Accreditation Service (UKAS) accredited (ISO 15189:2012) laboratory (Synnovis) at King’s College Hospital, was recorded within 3 months of a patient’s survey. This was correlated with the following variables: QLQ-C30 score for diarrhoea and global health status; QLQ-GINET21 endocrine symptoms (questions 31-33) and GI symptoms scale (questions 34-38); GAD-7 score and PHQ-9 score. Small intestinal tumours were also examined as a separate subgroup.

Statistical analysis

The categorical variables were given in absolute numbers with percentages and continuous variables were given with median and IQR. The continuous variables did not meet normal distribution and, hence, the correlation was assessed with Spearman rho (ρ). The distribution of the variables between sexes were evaluated with Mann-Whitney U test. Two-tailed test was performed and a p value of <0.05 was considered significant.

Results

Of 386 patients, 258 (66.8%) had completed a HRQL questionnaire with a corresponding temporally related u5HIAA available ( Figure 2 ). Patients with unknown primary sites and primary sites that do not typically secrete serotonin (n=26) were excluded ( Figure 2 ). The median age was 66 years (IQR: 54 – 72). 48.7% (n=113) of 232 patients were female and 51.3% (n=119) were male. One hundred and forty-nine (64.2%) were of white ethnicity. The majority of patients had a small intestinal primary (n=145; 62.5%) and 137 (59.1%) of the total cohort had low grade (G1) NEN. The median 5-HIAA was 7.8 (IQR: 3.9 – 13.6) in the cohort and 8.5 (IQR: 4.1 – 15.1) in the small intestine primary group. Characteristics of the entire cohort, and of patients with small bowel primary are given in Table 2 . Figure 2. Patient selection and exclusion process. Of 386 patients with NEN, 258 had both HRQL and temporally related u5HIAA data available. Patients with unknown primary sites or tumour types not typically associated with serotonin secretion were excluded from the final analysis (n=26). Excluded tumours comprised ovarian (n=2), thymic (n=1), thyroid (n=1), paraganglioma (n=3), phaeochromocytoma (n=1), rectal (n=5) and unknown primary NENs (n=13). Table 2. Primary site. Primary site n (%) Small intestine 145 (62.5%) Pancreas 49 (21.1%) Lung 13 (5.6%) Appendix 8 (3.4%) Gastric 7 (3.0%) Duodenum 6 (2.6%) Colon 3 (1.3%) Ampulla 1 (0.4%)

In the cohort 205 (88%) patients completed the C30 Global Health Status scale, whilst 93%, 96% and 98% completed the NET21, GAD7 and PHQ9 respectively. The median and IQR are given in Table 3 . Table 3. Patient characteristics. ​ Entire cohort (n=232) Small intestine (n=145) Age 66 yrs. (54 – 72) 68 yrs. (59 – 73) Sex Females 113 (48.7%) 68 (46.9%) Males 119 (51.3%) 77 (53.1%) Ethnicity Asian 8 (3.4%) 3 (2.1%) Black 15 (6.5%) 10 (6.9%) White 149 (64.2%) 93 (64.1%) Other 11 (4.7%) 8 (5.5%) Unknown 49 (21.2%) 31 (21.4%) Spot u5HIAA * (umol/mmol creat) 7.8 (3.9 – 13.6) 8.5 (4.1 – 15.1) Ki67% 1 (1 – 3) 1 (1 – 3) NET Grade: G1 137 (59.1%) 95 (65.5%) G2 51 (22.0%) 27 (18.6%) G3 5 (2.2%) 2 (1.4%) Unrecorded 39 (16.7%) 21 (14.5%) * The upper limit of the normal range for spot u5HIAA is 4 µmol/mmol creat. Values are presented as median (IQR: interquartile range).

There was a significant correlation between a higher u5HIAA and lower NET21 GI symptom and GAD7 scores ( Figure 3 , Figure 4 ). No other correlations were found. There were no significant associations between u5HIAA and HRQL in small intestine primaries. Table 4 shows the correlations in the overall and small intestine cohorts. Figure 3. Scatterplot showing the correlation between GAD-7 Anxiety Score and log u5HIAA values in the overall cohort. Higher u5HIAA concentrations were associated with lower anxiety scores (Spearman’s ρ = -0.144, p = 0.032). Figure 4. Scatterplot showing the correlation between GINET21 GI Scale and log u5HIAA values. Higher u5HIAA concentrations were associated with lower gastrointestinal symptom scores (Spearman’s ρ = -0.114, p = 0.024). Table 4. Health related quality of life (HRQL). HRQL questionnaire Entire cohort Small intestine QoL C30 (n=205) Global Health Scale 67 (50 - 83) 67 (50 - 83) Diarrhoea 33 (0 - 67) 33 (0 - 67) NET 21 (n=216) Endocrine symptom scale 11 (0 – 30.25) 11 (0 - 33) GI Symptom Scale 20 (7 - 40) 20 (7 - 33) GAD 7 (n=223) Anxiety Score 1 (0 - 2) 1 (0 - 2) Anxiety Severity Grade: No or mild anxiety 184 (82.5%) 114 (82.6%) Significant level of anxiety 39 (17.5%) 24 (17.4%) PHQ 9 (n=228) Depression Score 0 (0 - 2) 0 (0 - 2) Depression Severity Grade: No or mild depression 195 (85.5%) 121 (85.2%) Probable Major depression 33 (14.5%) 21 (14.8%)

Overall, males had a significantly higher u5HIAA umol/mmol creat (10.1 IQR: 6.2 – 16.2) compared to females (5.6 IQR: 3.3 – 11.6), p=0.001. Males also had a significantly higher Global Health score (p=0.018), and significantly lower QLQ-GINET21 GI and endocrine scale scores (p=0.001). In addition, males had lower GAD7 (p=0.001) and PHQ9 (p=0.009) scores ( Table 5 ). Table 5. Correlations of u5HIAA and HRQL. HRQL Entire cohort Small intestine Spearman’s rho (95% CI) p-value Spearman’s rho (95% CI) p-value C30 Global Health Scale 0.023 (-0.119 to 0.163) 0.746 0.011 (-0.170 to 0.190) 0.905 Diarrhoea Score -0.072 (-0.211 to 0.070) 0.305 -0.211 (-0.286 to 0.070) 0.213 NET 21 Endocrine scale -0.088 (-0.233 to 0.050) 0.197 -0.077 (-0.247 to 0.097) 0.371 GI Scale -0.114 (-0.244 to -0.054) 0.024 -0.093 (-0.262 to 0.082) 0.282 GAD 7 Anxiety Score -0.144 (-0.274 to -0.009) 0.032 -0.139 (-0.304 to 0.033) 0.103 PHQ 9 Depression Score 0.058 (-0.076 to 0.190) 0.383 0.070 (-0.101 to 0.236) 0.410 Negative Spearman’s rho values indicate lower symptom scores with increasing u5HIAA concentrations.

Discussion

This retrospective, single centre study represents the largest dataset examining the relationship between u5HIAA concentrations and psychological distress in patients with NEN. We observed a negative correlation between u5HIAA concentrations and anxiety scores suggesting that higher circulating serotonin might be protective against symptoms of anxiety. Although peripheral serotonin cannot cross the blood brain barrier to directly influence mood, our findings align with animal studies demonstrating rodents on low tryptophan diets, which reduce serotonin availability, exhibit increased anxiety-like behaviour. Nevertheless, human studies remain inconclusive in establishing a biochemical basis for serotonin depletion in neuropsychiatric disorders. 22

The tryptophan depletion model has been the prevailing theory linking elevated peripheral serotonin to psychological distress in NEN. Higher circulating peripheral serotonin in carcinoid syndrome has been postulated to reduce tryptophan availability for central nervous system (CNS) serotonin synthesis, potentially contributing to psychological distress. 23 – 25 Our cohort showed reduced anxiety with higher levels of peripheral serotonin, measured by u5HIAA, which contradicts a tryptophan depletion model as the basis of psychological distress in NEN. Furthermore, there was no correlation between u5HIAA and depression scores, which goes against a direct link between elevated peripheral serotonin and mood in NEN ( Table 6 ). Table 6. Variation between females and males. Cohort (n=258) Female Male p-value Age 65 yrs. (53 - 71) 66 yrs. (55 - 73) 0.203 u5HIAA 5.6 (3.3 - 11.3) 10.0 (5.6 – 15.4) 0.001 C30 Global Health Scale 67 (50 - 75) 75 (50 - 83) 0.018 Diarrhoea Score 33 (0 - 67) 33 (0 - 33) 0.146 NET 21 Endocrine scale 22 (0 - 33) 11 (0 - 22) 0.001 GI Scale 27 (13 - 47) 20 (7 - 27) 0.001 GAD 7 Anxiety Score 2 (0 - 11) 0 (0 - 1) 0.001 PHQ 9 Depression Score 1 (0 - 2) 0 (0 -2) 0.009

Lewis and colleagues 19 explored the role of serum serotonin in (n=50) patients with NEN and looked at correlations with HRQL, anxiety, depression and impulsivity. They found 25% of their cohort to have high anxiety scores (using Hospital Anxiety and Depression Scale) which was unrelated to u5HIAA concentrations. Korse and colleagues 26 correlated u5HIAA to HRQL, abdominal pain, flushes and diarrhoea in (n=39) NEN patients and found no significant association. The emerging consensus, therefore, is that u5HIAA has a limited role in predicting GI, endocrine and mood affective symptoms.

Whereas traditionally a high u5HIAA may have instigated a lower threshold for high-risk intervention, due to perceived secretory symptom burden, this may not be entirely appropriate. In our cohort, a high u5HIAA might indicate raised serotonin levels could be protective against anxiety. Therefore, utilising PROMs for assessing responses to therapies may be more appropriate than using u5HIAA. The significant proportion of patients with NEN reporting high levels of anxiety (17.5% of our entire cohort) indicates that anxiety is likely underdiagnosed in this population. Therefore, the need for psychosocial care is feasibly under-recognised despite extensive resources made available through patient advocacy groups and charities, such as Neuroendocrine Cancer UK.

The median global health score amongst our cohort was 67, which is in keeping with the reference score for all cancer patients of all stages (66.7). The median score for diarrhoea in our cohort (33) was expectedly significantly higher than average for all cancer patients (nine) and double the average for patients with colorectal cancer (16.6). 27 Therefore, despite the typically higher burden of GI symptoms associated with NEN, the quality of life in this cohort was not depleted beyond that of the average patient with cancer. There was no significant correlation between u5HIAA and diarrhoea, corroborating previous studies. 26 Consequently, whilst diarrhoea may be common in NEN, it may not be linked with circulating serotonin concentrations which highlights the significance of other causes of diarrhoea in NEN (e.g. short bowel, somatostatin analogues and pancreatic exocrine dysfunction). 28

Diarrhoea was self-reported as similar between males and females, however, there was a significant difference in the QLQ-GINET21 GI scale between sexes. The GI scale addresses symptoms such as abdominal bloating, discomfort, heartburn, flatulence and problems eating. 9 Sexual dimorphism in enteric serotonergic processing pathways, driven by the modulatory effects of sex steroids, may contribute to the higher QLQ-GINET21 GI scores observed in women in our study. 29 The endocrine scale, which evaluates hot flushes and night sweats, also revealed a significant difference between sexes in our cohort. These differences translate into GHQ (global score), GAD-7 and PHQ-9, which leads to the finding that females in this cohort reported more depression, anxiety and had a poorer quality of life compared to males. This was despite no significant differences in tumour grade, site and ethnicity between sexes. The level of discrepancy between self-reported symptoms and quality of life between males and females in this tertiary referral centre warrants further exploration, as it may open avenues to better support patients.

Epidemiological sex differences in neuropsychiatric conditions are well characterised, with anxiety and depression being more common in women. 30 This may be due to biological differences in the serotonin system between men and women. The 5-HT1A receptor is involved in mood disorders and 5-HT transporter (5-HTT) is a target for selective serotonin reuptake inhibitors (SSRI); both were shown to differ between sexes when measuring binding potential by selective radioligands and Positron Emission Tomography 31 Preclinical research has historically been inadequate in exploring the biological basis of sex-specific differences in mood disorders because female rodents were traditionally excluded from studies. Emerging studies including both male and female rodents have identified several neurobiological mechanisms that may contribute to female vulnerability to mood disorders. 32 Interestingly, women have a higher susceptibility than men to undergo serotoninergic alterations due to changes in the levels of its precursor, tryptophan 33 Therefore, alterations in tryptophan metabolism due to carcinoid syndrome could disproportionately affect women and contribute to explaining the higher anxiety and depression scores in our female cohort.

The differences in u5HIAA concentrations between males and females in this cohort warrants further attention. While existing literature presents conflicting evidence regarding sex-based differences in serotonin levels, several studies suggest that females have higher plasma and whole-blood serotonin concentrations but lower platelet serotonin levels compared to males. 34 – 36 There are no consistent sex differences in u5HIAA concentration levels in the CSF, although some studies report elevated levels in women. 37 , 38 Although the Mayo Clinic does report higher reference ranges for u5HIAA in males than females, there are no studies in current literature reporting such significant differences in u5HIAA as was demonstrated in this cohort of patients with NEN. 39

It is possible that lower u5HIAA, and hence circulating peripheral serotonin, levels in females could be secondary to their seeking medical attention for symptoms earlier than males and therefore being treated earlier in their disease course (Springer and Mouzon, 2011). 40 We cannot find another explanation for this large difference, although it may be a combination of genetic, immunological, environmental and behavioural differences. 41 – 43 Two systematic reviews analysing delayed presentation in patients with cancer found little evidence to suggest association between sex and time to presentation for lung, upper GI and lower GI cancers 44 – 48 However, when it came to urological cancer, men were found to delay longer than women 49 – 51

There is a paucity of high-quality trials prospectively investigating sex differences in NEN, despite evidence suggesting female patients are more likely to be diagnosed with carcinoid syndrome than males, 52 58% Vs 42% respectively in one study. 53 A number of population-based studies have shown females with NEN to have a significantly increased survival when compared to males 54 . These favourable outcomes extend to liver-directed therapies 55 , 56 but not treatment with somatostatin analogues in clinical trials to date 57 – 59

One limitation of this study is its retrospective design, which inherently restricts the ability to establish causal relationships. Information on therapeutic management, disease status, and time since diagnosis at the time of u5HIAA collection and HRQL assessment was unavailable, precluding distinction between newly diagnosed and stable patients—an important factor, as adaptation over time may influence HRQL and psychological outcomes. Data regarding patient medication history at the time of u5HIAA sampling would also have identified those receiving psychotropic therapy such as SSRIs, a variable with potential to affect GAD-7 and PHQ-9 results. Furthermore, information regarding adherence to dietary restrictions prior to u5HIAA sampling was unavailable and may have contributed to variability in measured u5HIAA concentrations. Furthermore, incomplete ethnicity data ( Table 3 ) preclude exclusion of cultural factors that might influence sex differences in HRQL. Another limitation is the large number of patients who did not complete HRQL questionnaires, which clearly introduces selection bias within our cohort. Finally, while our findings are significant and informative to clinical practice, it is important to note that the negative correlations between u5HIAA and both GAD-7 and GINET21 were weak.

Conclusion

u5HIAA did not correlate to clinical ‘endocrine’ symptomology, depression or global HRQL scores in patients with NEN. There was a negative correlation between u5HIAA and anxiety and GI symptom scores. These findings suggest that high u5HIAA concentrations in the outpatient clinic environment are not linked with a higher burden of symptoms or psychological distress. The observed association between elevated u5HIAA concentrations, reflecting increased peripheral serotonin production, and lower anxiety scores warrants further investigation, as the mechanism underlying this relationship remains uncertain. Appropriately powered prospective studies are required to confirm these findings. Further research is needed to investigate sex-differences in the serotonergic pathophysiology of NEN and how this translates into the sex disparities in patient reported HRQL seen in this cohort.

Acknowledgments

We would like to thank patients attending KHP ENETS centre of excellence who filled in QoL data. We thank the staff of the IMPARTS service for setting up the collection system and extracting the original data. This project was presented at the 20th Annual European Neuroendocrine Tumor Society (ENETS) Conference and the abstract is available in “Supplement: 20th Annual ENETs Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease 22–24 March 2023”.

Funding: The authors received no financial support for the research or authorship of this article.

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Artificial Intelligence (AI) statement: Artificial intelligence (AI) tools (ChatGPT, OpenAI, and Claude, Anthropic) were used to assist with language editing, manuscript revision and formatting. AI tools were not used for study design, data collection, statistical analysis, interpretation of results, or generation of scientific conclusions. All outputs were reviewed and edited by the authors, who take full responsibility for the accuracy and integrity of the manuscript.

ORCID iD

Rayhan Chaudhry https://orcid.org/0000-0001-9721-8425

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Integrating Mental and Physical Healthcare: Research, Training and Services (IMPARTS) Research Oversight Committee of King’s Health Partners (date of approval: 27/11/2020). IMPARTS holds lasting approval from the Health Research Authority (HRA) to independently approve projects under an agreed research governance framework (Reference 18/SC/0039).

Consent to participate

Electronic informed consent was obtained from all subjects involved in the study via the IMPARTS database and all survey data were pseudonymized by IMPARTS.

Data Availability Statement

Raw data were extracted from the IMPARTS service. Derived data supporting the findings of this study are available from the corresponding author [JR] on request. *

References

1 Rindi G Mete O Uccella S , et al. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms . Endocrine Pathology 2022 ; 33 : 115 – 154 . 10.1007/s12022-022-09708-2 35294740

2 White BE Rous B Chandrakumaran K , et al. Incidence and survival of neuroendocrine neoplasia in England 1995–2018: A retrospective, population-based study . The Lancet Regional Health - Europe 2022 ; 23 : 100510 . 10.1016/j.lanepe.2022.100510 36176500 PMC9513765

3 Halperin DM Shen C Dasari A , et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study . Lancet Oncol 2017 ; 18 : 525 – 534 . 10.1016/S1470-2045(17)30110-9 28238592 PMC6066284

4 Clement D Ramage J Srirajaskanthan R . Update on Pathophysiology, Treatment, and Complications of Carcinoid Syndrome . J Oncol 2020 ; 2020 : 1 – 11 . 10.1155/2020/8341426 PMC7160731 32322270

5 Meijer WG Kema IP Volmer M , et al. Discriminating Capacity of Indole Markers in the Diagnosis of Carcinoid Tumors . Clin Chem 2000 ; 46 : 1588 – 1596 . 11017936

6 Calanchini M Tadman M Krogh J , et al. Measurement of urinary 5-HIAA: correlation between spot versus 24-h urine collection . Endocr Connect 2019 ; 8 : 1082 – 1088 . 10.1530/EC-19-0269 31265996 PMC6652243

7 Rinke A Müller HH Schade-Brittinger C , et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group . J Clin Oncol 2009 ; 27 : 4656 – 4663 . 10.1200/jco.2009.22.8510 19704057

8 Aaronson NK Ahmedzai S Bergman B , et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology . J Natl Cancer Inst 1993 ; 85 : 365 – 376 . 10.1093/jnci/85.5.365 8433390

9 Yadegarfar G Friend L Jones L , et al. Validation of the EORTC QLQ-GINET21 questionnaire for assessing quality of life of patients with gastrointestinal neuroendocrine tumours . Br J Cancer 2013 ; 108 : 301 – 310 . 10.1038/bjc.2012.560 23322194 PMC3566824

10 Kroenke K Spitzer RL Williams JBW . The PHQ-9: Validity of a brief depression severity measure . J Gen Intern Med 2001 ; 16 : 606 – 613 . 10.1046/j.1525-1497.2001.016009606.x 11556941 PMC1495268

11 Spitzer RL Kroenke K Williams JBW , et al. A Brief Measure for Assessing Generalized Anxiety Disorder . Arch Intern Med 2006 ; 166 : 1092 – 1097 . 10.1001/archinte.166.10.1092 16717171

12 Martin AM Young RL Leong L , et al. The Diverse Metabolic Roles of Peripheral Serotonin . Endocrinology 2017 ; 158 : 1049 – 1063 . 10.1210/en.2016-1839 28323941

13 Ruhé HG Mason NS Schene AH . Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies . Mol Psychiatry 2007 ; 12 : 331 – 359 . 10.1038/sj.mp.4001949 17389902

14 Fusar-Poli P Allen P McGuire P , et al. Neuroimaging and electrophysiological studies of the effects of acute tryptophan depletion: a systematic review of the literature . Psychopharmacology (Berl) 2006 ; 188 : 131 – 143 . 10.1007/s00213-006-0493-1 16915379

15 Major LF LaVonne Brown G Wilson WP . Carcinoid and psychiatric symptoms . South Med J 1973 ; 66 : 787 – 790 . 10.1097/00007611-197307000-00013 4752229

16 Larsson G Sjödén PO Öberg K , et al. Health-related quality of life, anxiety and depression in patients with midgut carcinoid tumours . Acta Oncol 2001 ; 40 : 825 – 831 . 10.1080/02841860152703445 11859981

17 Russo S Nielen MMA Boon JC , et al. Neuropsychological investigation into the carcinoid syndrome . Psychopharmacology (Berl) 2003 ; 168 : 324 – 328 . 10.1007/s00213-003-1455-5 12695876

18 Russo S Boon JC Kema IP , et al. Patients with carcinoid syndrome exhibit symptoms of aggressive impulse dysregulation . Psychosom Med 2004 ; 66 : 422 – 425 . 10.1097/01.psy.0000126204.97565.91 15184706

19 Lewis AR Wang X Magdalani L , et al. Health-related quality of life, anxiety, depression and impulsivity in patients with advanced gastroenteropancreatic neuroendocrine tumours . World J Gastroenterol 2018 ; 24 : 671 – 679 . 10.3748/wjg.v24.i6.671 29456406 PMC5807670

20 Rayner L Matcham F Hutton J , et al. Embedding integrated mental health assessment and management in general hospital settings: Feasibility, acceptability and the prevalence of common mental disorder . Gen Hosp Psychiatry 2014 ; 36 : 318 – 324 . 10.1016/j.genhosppsych.2013.12.004 24630892

21 von Elm E Altman DG Egger M , et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies . J Clin Epidemiol 2008 ; 61 : 344 – 349 . 10.1016/j.jclinepi.2007.11.008 18313558

22 Moncrieff J Cooper RE Stockmann T , et al. The serotonin theory of depression: a systematic umbrella review of the evidence . Molecular Psychiatry 2022 ; 28 : 3243 – 3256 . 10.1038/s41380-022-01661-0 35854107 PMC10618090

23 Bender DA . Biochemistry of tryptophan in health and disease . Mol Aspects Med 1983 ; 6 : 101 – 197 . 10.1016/0098-2997(83)90005-5 6371429

24 Kvols LK . Metastatic Carcinoid Tumors and the Malignant Carcinoid Syndrome . Ann N Y Acad Sci 1994 ; 733 : 464 – 470 . 10.1111/j.1749-6632.1994.tb17296.x 7978896

25 Tanke MAC Kema IP Dijck-Brouwer J , et al. Low plasma tryptophan in carcinoid patients is associated with increased urinary cortisol excretion . Psychoneuroendocrinology 2008 ; 33 : 1297 – 1301 . 10.1016/j.psyneuen.2008.07.005 18722719

26 Korse CM Bonfrer JMG Aaronson NK , et al. Chromogranin A as an alternative to 5-hydroxyindoleacetic acid in the evaluation of symptoms during treatment of patients with neuroendocrine Tumors . Neuroendocrinology 2009 ; 89 : 296 – 301 . 10.1159/000162876 18840995

27 Scott N Fayers P Aaronson N , et al. EORTC QLQ-C30 Reference Values This manual presents reference data for the QLQ-C30 based upon data provided by EORTC Quality of Life Group Members and other users of the QLQ-C30 Sprangers on behalf of the EORTC Quality of Life Group EORTC Quality of Life Group . 2008 . https://www.eortc.org/app/uploads/sites/2/2018/02/reference_values_manual2008.pdf

28 Khan MS Walter T Buchanan-Hughes A , et al. Differential diagnosis of diarrhoea in patients with neuroendocrine tumours: A systematic review . World J Gastroenterol 2020 ; 26 : 4537 – 4556 . 10.3748/wjg.v26.i30.4537 32874063 PMC7438200

29 So SY Savidge TC . Sex-Bias in Irritable Bowel Syndrome: Linking Steroids to the Gut-Brain Axis . Front Endocrinol (Lausanne) 2021 ; 12 : 684096 . 10.3389/fendo.2021.684096 34093447 PMC8170482

30 Kessler RC Petukhova M Sampson NA , et al. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States . Int J Methods Psychiatr Res 2012 ; 21 : 169 – 184 . 10.1002/mpr.1359 22865617 PMC4005415

31 Jovanovic H Lundberg J Karlsson P , et al. Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET . Neuroimage 2008 ; 39 : 1408 – 1419 . 10.1016/j.neuroimage.2007.10.016 18036835

32 Bangasser DA Cuarenta A . Sex differences in anxiety and depression: circuits and mechanisms . Nat Rev Neurosci 2021 ; 22 : 674 – 684 . 10.1038/s41583-021-00513-0 34545241

33 Pais ML Martins J Castelo-Branco M , et al. Sex Differences in Tryptophan Metabolism: A Systematic Review Focused on Neuropsychiatric Disorders . Int J Mol Sci 2023 ; 24 : 6010 . 10.3390/ijms24066010 36983084 PMC10057939

34 Chakraborti B Verma D Guhathakurta S , et al. Gender-Specific Effect of 5-HT and 5-HIAA on Threshold Level of Behavioral Symptoms and Sex-Bias in Prevalence of Autism Spectrum Disorder . Front Neurosci 2020 ; 13 : 1375 . 10.3389/fnins.2019.01375 31998058 PMC6961535

35 Houghton LA Brown H Atkinson W , et al. 5-hydroxytryptamine signalling in irritable bowel syndrome with diarrhoea: effects of gender and menstrual status . Aliment Pharmacol Ther 2009 ; 30 : 919 – 929 . 10.1111/j.1365-2036.2009.04121.x 19691669

36 Pivac N Mück-Šeler D Mustapić M , et al. Platelet serotonin concentration in alcoholic subjects . Life Sci 2004 ; 76 : 521 – 531 . 10.1016/j.lfs.2004.06.024 15556165

37 Blennow K Wallin A Gottfries CG , et al. Cerebrospinal fluid monoamine metabolites in 114 healthy individuals 18-88 years of age . Eur Neuropsychopharmacol 1993 ; 3 : 55 – 61 . 10.1016/0924-977x(93)90295-w 7682460

38 Brewerton TD Putnam KT Lewine RRJ , et al. Seasonality of cerebrospinal fluid monoamine metabolite concentrations and their associations with meteorological variables in humans . J Psychiatr Res 2018 ; 99 : 76 – 82 . 10.1016/j.jpsychires.2018.01.004 29427844 PMC5849528

39 Mayo Clinic Laboratories. 5-Hydroxyindoleacetic Acid, 24 Hour, Urine . https://www.mayocliniclabs.com/test-catalog/Overview/9248#Clinical-and-Interpretive ( accessed 21 June 2026) .

40 Springer KW Mouzon DM . “Macho Men” and Preventive Health Care . J Health Soc Behav 2011 ; 52 : 212 – 227 . 10.1177/0022146510393972 21490311

41 Klein SL Flanagan KL . Sex differences in immune responses . Nat Rev Immunol 2016 ; 16 : 626 – 638 . 10.1038/nri.2016.90 27546235

42 Baggio G Corsini A Floreani A , et al. Gender medicine: a task for the third millennium . Clinical Chemistry and Laboratory Medicine (CCLM) 2013 ; 51 : 713 – 727 . 10.1515/cclm-2012-0849 23515103

43 Oertelt-Prigione S . The influence of sex and gender on the immune response . Autoimmun Rev 2012 ; 11 : A479 – A485 . 10.1016/j.autrev.2011.11.022 22155201

44 Worden JW Weisman AD . Psychosocial components of lagtime in cancer diagnosis . J Psychosom Res 1975 ; 19 : 69 – 79 . 10.1016/0022-3999(75)90052-5 1142317

45 Mor V Masterson-Allen S Goldberg R , et al. Pre-diagnostic symptom recognition and help seeking among cancer patients . J Community Health 1990 ; 15 : 253 – 266 . 10.1007/BF01350291 2212095

46 Bowen EF Rayner CFJ . Patient and GP led delays in the recognition of symptoms suggestive of lung cancer . Lung Cancer 2002 ; 37 : 227 – 228 . 10.1016/s0169-5002(02)00143-5 12140147

47 Macdonald S Macleod U Campbell NC , et al. Systematic review of factors influencing patient and practitioner delay in diagnosis of upper gastrointestinal cancer . Br J Cancer 2006 ; 94 : 1272 – 1280 . 10.1038/sj.bjc.6603089 16622459 PMC2361411

48 Mitchell E Macdonald S Campbell NC , et al. Influences on pre-hospital delay in the diagnosis of colorectal cancer: a systematic review . Br J Cancer 2007 ; 98 : 60 – 70 . 10.1038/sj.bjc.6604096 18059401 PMC2359711

49 Månsson Å Anderson H Colleen S . Time Lag to Diagnosis of Bladder Cancer–Influence of Psychosocial Parameters and Level of Health-Care Provision . Scand J Urol Nephrol 1993 ; 27 : 363 – 369 . 10.3109/00365599309180448 8290917

50 Risberg T Sørbye SW Norum J , et al. Diagnostic delay causes more psychological distress in female than in male cancer patients . Anticancer Res 1996 ; 16 : 995 – 999 . 8687166

51 Mommsen S Aagaard J Sell A . Presenting Symptoms, Treatment Delay and Survival in Bladder Cancer . Scand J Urol Nephrol 1983 ; 17 : 163 – 167 . 10.3109/00365598309180162 6612234

52 Ruggeri RM Altieri B Grossrubatcher E , et al. Sex differences in carcinoid syndrome: A gap to be closed . Rev Endocr Metab Disord 2022 ; 23 : 659 – 669 . 10.1007/s11154-022-09719-8 35292889

53 Kimbrough CW Beal EW Dillhoff ME , et al. Influence of carcinoid syndrome on the clinical characteristics and outcomes of patients with gastroenteropancreatic neuroendocrine tumors undergoing operative resection . Surgery 2019 ; 165 : 657 – 663 . 10.1016/j.surg.2018.09.008 30377003 PMC10182411

54 Hallet J Law CHL Cukier M , et al. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes . Cancer 2015 ; 121 : 589 – 597 . 10.1002/cncr.29099 25312765

55 Carrasco CH Charnsangavej C Ajani J , et al. The carcinoid syndrome: palliation by hepatic artery embolization . American Journal of Roentgenology 1986 ; 147 : 149 – 154 . 10.2214/ajr.147.1.149 2424291

56 Roche A Girish BV de Baère T , et al. Trans-catheter arterial chemoembolization as first-line treatment for hepatic metastases from endocrine tumors . Eur Radiol 2003 ; 13 : 136 – 140 . 10.1007/s00330-002-1558-0 12541121

57 Oberg K Couvelard A Delle Fave G , et al. ENETS consensus guidelines for standard of Care in Neuroendocrine Tumours: biochemical markers . Neuroendocrinology 2017 ; 105 : 201 – 211 . 10.1159/000472254 28391265

58 Vinik AI Wolin EM Liyanage N , et al. Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (Elect): A Randomized, Double-Blind, Placebo-Controlled Trial . Endocrine Practice 2016 ; 22 : 1068 – 1080 . 10.4158/ep151172.or 27214300

59 Fisher GA Wolin EM Liyanage N , et al. Lanreotide Therapy in Carcinoid Syndrome: Prospective Analysis of Patient-Reported Symptoms in Patients Responsive To Prior Octreotide Therapy And Patients Naïve To Somatostatin Analogue Therapy in The Elect Phase 3 Study . Endocrine Practice 2018 ; 24 : 243 – 255 . 10.4158/ep172000.or 29547049